Activation of CD4+ T lymphocytes is necessary for the development of most immune responses and requires specialized antigen-presenting cells (APC). Langerhans cells (LC) are probably the first APCs to encounter antigen during a conventional immune response, as most pathogens enter the body via the epidermis, by inhalation or ingestion. LC are induced to leave epithelia as a result of local trauma. They migrate via afferent lymphatics to the draining lymph node, where they activate naive T cells to the antigens encountered in the epithelium. The signals involved in their migration are poorly characterized. The goal of this project is to determine the epithelial cells and signals that induce LC to migrate to lymph nodes. The ultimate purpose of this research is to develop methods for modulating LC migration in local sites. Two mutant animal models will be used for the analysis of LC migration. The mutant mice carry independent genetic defects both of which abolish LC migration to lymph nodes. The Specific Aims of this proposal are 1) to characterize the defect in the migration of LC in the first mutant; 2) to develop an in vitro system to determine the factors controlling murine LC migration; 3) to characterize the defect in LC migration in the second mutant; and 4) to develop an in vitro system to determine the factors controlling human LC migration.